Identification of cells carrying out low-levels of HIV-1 replication and renewing viral reservoirs in patients taking highly active antiretroviral therapy (HAART) is important for enhancing the efficiency of suppressive therapy. While CD4+ T cells and tissue macrophages are potential viral reservoirs, the roles of monocytes in HIV-1 infection in vivo remain obscure. Recent studies suggest the existence of other sources of virus besides resting CD4+ T cells. Our recent studies indicate that ongoing HIV- 1 replication occurs in vivo in CD 14+ monocytes in the presence of HAART, and that HIV-1 replication in CD 14+ monocytes is an important source of persistent HIV-1 replication among persons on HAART. HIV- I infection of CDI 4 monocytes appears to occur shortly after acquisition of infection. Viral dynamics suggest a rate of viral evolution is higher in CD 14+ monocytes than in resting CD4+ T cells and approaches that of activated CD4+ T cells under HAART therapy. The goal of this proposal is to extend our current understanding of the dynamics of HIV-1 in CD14+ monocytes, and to define the roles of CD 14+ monocytes in HIV- 1 infection in the presence and absence of antiretroviral drugs by the following specific aims: 1) to determine the impact of antiretroviral therapy on the dynamics of HIV-1 replication in CD14+ monocytes in vivo; 2) to evaluate if CD14+ monocytes are the major sources of HIV- 1 replication in patients receiving different or no antiretroviral therapy. These viral dynamic studies will be centered around acutely infected patients who received early versus delayed therapy, those who received no therapy or discontinuous therapy, and those who received protease inhibitors, or nonprotease inhibitors. Findings from this proposal will provide better understanding of productive infection of HIV-1 in CD 14+ monocytes in vivo, and may also provide great insights to developing new therapeutic strategies to enhance therapy efficacy.